Alterations in the Medullary Endocannabinoid System Contribute to Age-related Impairment of Baroreflex Sensitivity

Abstract: As they age, Sprague–Dawley (SD) rats develop elevated systolic blood pressure associated with impaired baroreflex sensitivity (BRS) for control of heart rate. We previously demonstrated in young hypertensive (mRen2)27 rats that impaired BRS is restored by CB1 cannabinoid receptor blockade in the solitary tract nucleus (NTS), consistent with elevated content of the endocannabinoid 2-arachidonoylglycerol (2-AG) in dorsal medulla relative to normotensive SD rats. There is no effect of CB1 receptor blockade in young SD rats. We now report in older SD rats that dorsal medullary 2-AG levels are 2-fold higher at 70 versus 15 weeks of age (4.22 ± 0.61 vs. 1.93 ± 0.22 ng/mg tissue; P < 0.05). Furthermore, relative expression of CB1 receptor messenger RNA is significantly lower in aged rats, whereas CB2 receptor messenger RNA is significantly higher. In contrast to young adult SD rats, microinjection of the CB1 receptor antagonist SR141716A (36 pmole) into the NTS of older SD rats normalized BRS in animals exhibiting impaired baseline BRS (0.56 ± 0.06 baseline vs. 1.06 ± 0.05 ms/mm Hg after 60 minutes; P < 0.05). Therefore, this study provides evidence for alterations in the endocannabinoid system within the NTS of older SD rats that contribute to age-related impairment of BRS.

[1]  Amy C. Arnold,et al.  Endogenous leptin contributes to baroreflex suppression within the solitary tract nucleus of aged rats. , 2014, American journal of physiology. Heart and circulatory physiology.

[2]  J. Taylor,et al.  BP regulation VI: elevated sympathetic outflow with human aging: hypertensive or homeostatic? , 2014, European Journal of Applied Physiology.

[3]  F. Vogt,et al.  Chronic blockade of angiotensin AT1 receptors improves cardinal symptoms of metabolic syndrome in diet‐induced obesity in rats , 2014, British journal of pharmacology.

[4]  J. Brüning,et al.  The paradox of neuronal insulin action and resistance in the development of aging-associated diseases , 2014, Alzheimer's & Dementia.

[5]  A. Derbenev,et al.  TRPV1-dependent regulation of synaptic activity in the mouse dorsal motor nucleus of the vagus nerve , 2013, Front. Neurosci..

[6]  V. Rovella,et al.  Obesity-Related Metabolic Syndrome: Mechanisms of Sympathetic Overactivity , 2013, International journal of endocrinology.

[7]  P. Gosse,et al.  Impaired baroreflex sensitivity and the risks of new-onset ambulatory hypertension, in an elderly population-based study. , 2013, International journal of cardiology.

[8]  B. Thomas,et al.  Abstract 182: Medullary Endocannabinoid Content Contributes to the Differential Resting Baroreflex Sensitivity in Rats with Altered Brain Renin-Angiotensin System Expression , 2013, Hypertension.

[9]  C. Bass,et al.  Striatal CB1 and D2 receptors regulate expression of each other, CRIP1A and delta opioid systems , 2013, Journal of neurochemistry.

[10]  Shuai Liu,et al.  Insulin induces long-term depression of VTA dopamine neurons via an endocannabinoid-mediated mechanism , 2013, Nature Neuroscience.

[11]  A. Phillips,et al.  Insulin Induces Long-term Depression of Vta Dopamine Neurons via an Endocannabinoid-mediated Mechanism Pubmed Central Canada Supplementary Material , 2022 .

[12]  A. Bilkei-Gorzo,et al.  The endocannabinoid system in normal and pathological brain ageing , 2012, Philosophical Transactions of the Royal Society B: Biological Sciences.

[13]  H. Shaltout,et al.  Central Angiotensin-(1–7) Improves Vagal Function Independent of Blood Pressure in Hypertensive (mRen2)27 Rats , 2012, Hypertension.

[14]  L. Hunyady,et al.  Angiotensin II Induces Vascular Endocannabinoid Release, Which Attenuates Its Vasoconstrictor Effect via CB1 Cannabinoid Receptors* , 2012, The Journal of Biological Chemistry.

[15]  M. Gorospe,et al.  Cannabinoids Induce Pancreatic β-Cell Death by Directly Inhibiting Insulin Receptor Activation , 2012, Science Signaling.

[16]  Lakshmi A Devi,et al.  AT1R–CB1R heteromerization reveals a new mechanism for the pathogenic properties of angiotensin II , 2011, The EMBO journal.

[17]  Koen Van Laere,et al.  Whole-Body Biodistribution and Radiation Dosimetry of the Cannabinoid Type 2 Receptor Ligand [11C]-NE40 in Healthy Subjects , 2011, Molecular Imaging and Biology.

[18]  D. Thompson,et al.  Expression of cannabinoid CB1 receptors by vagal afferent neurons: kinetics and role in influencing neurochemical phenotype. , 2010, American journal of physiology. Gastrointestinal and liver physiology.

[19]  Amy C. Arnold,et al.  Leptin Impairs Cardiovagal Baroreflex Function at the Level of the Solitary Tract Nucleus , 2009, Hypertension.

[20]  P. J. Larsen,et al.  The effect of leptin receptor deficiency and fasting on cannabinoid receptor 1 mRNA expression in the rat hypothalamus, brainstem and nodose ganglion , 2009, Neuroscience Letters.

[21]  D. Ganten,et al.  Angiotensin-(1-7) and Baroreflex Function in Nucleus Tractus Solitarii of (mRen2)27 Transgenic Rats , 2008, Journal of cardiovascular pharmacology.

[22]  M. Elphick,et al.  CB1 Cannabinoid Receptor Activity Is Modulated by the Cannabinoid Receptor Interacting Protein CRIP 1a , 2007, Molecular Pharmacology.

[23]  S. D. Moore,et al.  Differential Sensitivity of GABAA Receptor-Mediated IPSCs to Cannabinoids in Hippocampal Slices From Adolescent and Adult Rats , 2007 .

[24]  K. Monahan,et al.  Effect of aging on baroreflex function in humans. , 2007, American journal of physiology. Regulatory, integrative and comparative physiology.

[25]  L. Hunyady,et al.  The Role of Diacylglycerol Lipase in Constitutive and Angiotensin AT1 Receptor-stimulated Cannabinoid CB1 Receptor Activity* , 2007, Journal of Biological Chemistry.

[26]  D. Ganten,et al.  Baroreceptor reflex regulation in anesthetized transgenic rats with low glia-derived angiotensinogen. , 2007, American journal of physiology. Heart and circulatory physiology.

[27]  M. Maccarrone,et al.  The endocannabinoid system in ageing: a new target for drug development. , 2006, Current drug targets.

[28]  E. Ponomarev,et al.  Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli , 2005, Journal of neurochemistry.

[29]  Arya M. Sharma,et al.  Activation of the peripheral endocannabinoid system in human obesity. , 2005, Diabetes.

[30]  H. Shaltout,et al.  Mechanism of Fatty Acids Induced Suppression of Cardiovascular Reflexes in Rats , 2005, Journal of Pharmacology and Experimental Therapeutics.

[31]  D. Diz,et al.  Downloaded from http://hyper.ahajournals.org / by guest on February 20, 2013Impaired Heart Rate Baroreflex in Older Rats Role of Endogenous Angiotensin-(1–7) at the Nucleus Tractus Solitarii , 2022 .

[32]  K. Mackie,et al.  Endocannabinoids Acting at Cannabinoid-1 Receptors Regulate Cardiovascular Function in Hypertension , 2004, Circulation.

[33]  A. Derbenev,et al.  Cannabinoids suppress synaptic input to neurones of the rat dorsal motor nucleus of the vagus nerve , 2004, The Journal of physiology.

[34]  J. Seagard,et al.  Anandamide content and interaction of endocannabinoid/GABA modulatory effects in the NTS on baroreflex-evoked sympathoinhibition. , 2004, American journal of physiology. Heart and circulatory physiology.

[35]  T. Saido,et al.  Region‐specific reduction of Aβ‐degrading endopeptidase, neprilysin, in mouse hippocampus upon aging , 2002, Journal of neuroscience research.

[36]  M. Matheny,et al.  Hypothalamic leptin resistance is associated with impaired leptin signal transduction in aged obese rats , 2001, Neuroscience.

[37]  R. Palmiter,et al.  Leptin-regulated endocannabinoids are involved in maintaining food intake , 2001, Nature.

[38]  J. Paton,et al.  Convergence properties of solitary tract neurones driven synaptically by cardiac vagal afferents in the mouse , 1998, The Journal of physiology.

[39]  A. McKernan,et al.  Insulin microinjection into the nucleus tractus solitarii of the rat attenuates the baroreceptor reflex. , 1996, Journal of the autonomic nervous system.

[40]  F. Abboud,et al.  Structural versus functional modulation of the arterial baroreflex. , 1995, Hypertension.

[41]  P. Soubrié,et al.  Biochemical and pharmacological characterisation of SR141716A, the first potent and selective brain cannabinoid receptor antagonist. , 1995, Life sciences.

[42]  H. Itoh,et al.  Age-related reduction of reflex bradycardia in conscious rats by catecholaminergic nucleus tractus solitarius lesions , 1993, Mechanisms of Ageing and Development.

[43]  H. Itoh,et al.  Aging reduces cardiovascular and symphathetic responses to NTS injections of serotonin in rats , 1992, Experimental Gerontology.

[44]  M. Campagnole-Santos,et al.  Differential baroreceptor reflex modulation by centrally infused angiotensin peptides. , 1992, The American journal of physiology.

[45]  J. Vanderhaeghen,et al.  Distribution of neuronal cannabinoid receptor in the adult rat brain: A comparative receptor binding radioautography and in situ hybridization histochemistry , 1992, Neuroscience.

[46]  D. Barringer,et al.  Autonomic regulation of reflex bradycardia in rats declines with age , 1991, Experimental Gerontology.

[47]  F. Abboud,et al.  Rapid adaptation of central pathways explains the suppressed baroreflex with aging , 1991, Neurobiology of Aging.

[48]  R. Putnam,et al.  Which value for the first dissociation constant of carbonic acid should be used in biological work? , 1991, The American journal of physiology.

[49]  F. Abboud,et al.  Increase in sympathetic activity with age. I. Role of impairment of arterial baroreflexes. , 1991, The American journal of physiology.

[50]  S. Lundin,et al.  Effects of ageing on cardiac performance and coronary flow in spontaneously hypertensive and normotensive rats. , 1985, Acta physiologica Scandinavica.

[51]  Amy C. Arnold,et al.  Brain renin–angiotensin system in the nexus of hypertension and aging , 2013, Hypertension Research.

[52]  S. D. Moore,et al.  Differential sensitivity of GABA A receptor-mediated IPSCs to cannabinoids in hippocampal slices from adolescent and adult rats. , 2007, Journal of neurophysiology.

[53]  C. Ferrario,et al.  A comparison of the properties and enzymatic activities of three angiotensin processing enzymes: angiotensin converting enzyme, prolyl endopeptidase and neutral endopeptidase 24.11. , 1993, Life sciences.